p80 is a highly phosphorylated fusion protein present in anaplastic large cell lymphoma containing a t(2:5) chromosomal translocation that fuses nucleophosmin with an uncharacterized tyrosine kinase. We have expressed the cDNA encoding p80 in rat fibroblast and found that p80 can avidly transform cells. p80 transformed cells show serum independent growth, form foci on monolayers, and demonstrate profound substrate independent colony formation. Recent evidence suggests that p80 may function through a Ras-dependent pathway to induce the DNA-binding activity and transcriptional activation of several downstream targets of mitogenic stimulation including AP-1 and NF-kB. Cell cycle analysis indicates the p80 transformed cell passes rapidly though the G1 check point and accumulates in S and G2 phase. Recent evidence shows a close correlation between p80 dependent changes in the growth properties of fibroblast and the phosphorylation induced inactivation of the retinoblastoma tumor suppressor gene product (Rb). Preliminary studies suggest that other downstream targets of p80 dependent pathways may also serve to stabilize p53 DNA binding activity. Over expression of p80 in human T-cells leads to greater than 500% increase in transcriptional activation of the HIV-LTR, presumably through a Ras-dependent pathway. The presence of p80 cross-reactive staining in human brain suggests a possible population of cerebellar cells may be more highly susceptible to sustained infection by HIV and may contribute to some forms of HIV-associated cerebellar ataxia.